Cardiovascular disease is the number one cause of death in the industrialized world. According to the World Health Organization, more than 12 million people suffer each year from heart attacks and strokes. Controlling the risk factors for cardiovascular disease is a key preventive and therapeutic target in reducing this high mortality rate. Well-established risk factors for cardiovascular disease include elevated plasma levels for cholesterol (hypercholesterolemia), triglycerides, homocysteine, and certain lipoproteins (such as low-density lipoprotein (LDL) and lipoprotein(a) [hereinafter abbreviated as “Lp(a)”].
The majority of blood lipids are transported in plasma bound to lipoprotein particles. Lipoproteins are high molecular weight carriers of plasma cholesterol and triglycerides in the form of cholesteryl esters. They are micellar lipid-protein complexes which comprise one or more proteins associated with polar lipids surrounding a cholesterol-containing core. Five major density classes of lipoproteins have been recognized: chylomicrons, very low-density lipoproteins (VLDL), intermediate density lipoprotein (IDL) low-density lipoproteins (LDL) and high-density lipoproteins (HDL).
In addition to these five major classes of lipoproteins, Lp(a) has been identified. The structure of Lp(a) is closely related to LDL in that it consists LDL with an additional disulfide linked apolipoprotein(a), also known as “apo(a)”, which is a high-molecular weight adhesive protein. Apo(a) is in turn covalently bound to glycoprotein Apo B100, also known as “apolipoprotein B-100”, which is an integral part of LDL. While Apo B100 allows the LDL molecule to carry the hydrophobic cholesterol in the plasma and tissue fluids, apo(a) is water soluble and does not bind lipid. The major site of synthesis of plasma apo(a) appears to be the liver. It is presently unknown as to where Lp(a) is assembled. Lp(a) cholesterol appears to be a bad form of cholesterol, since elevated Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infraction, cerebral infarction, and restenosis following balloon angioplasty.
The structure of Lp(a) shares high homology to that of plasminogen, providing a linkage between the atherogenesis and clotting system. It has been hypothesized that Lp(a) can inhibit the fibrinolysis system. Lp(a) is shown to bind competitively to the plasminogen binding site and reduces the amount of plasmin generated by tissue plasminogen activator. Furthermore, Lp(a) is shown to be able to bind to fibrin and may prevent degradation of an existing thrombus by plasmin.
Among various lipoproteins, Lp(a) is often associated with the highest risk for cardiovascular disease. Several facts about Lp(a) are particularly noteworthy in connection with this invention (for review see: Rath, M. et al., “Detection and Quantification of Lipoprotein(a) in the Arterial Wall of 107 Coronary Bypass Patients,” Arteriosclerosis 9: 579-592 (1989), incorporated herein by reference in its entirety. For example, Lp(a) selectively accumulates in atherosclerotic plaques and contributes to the size of these plaques eventually leading to heart attacks and strokes; and the amount of Lp(a) deposited inside the artery walls is dependent from the plasma level of this lipoprotein. Studies have shown that Lp(a) bonded to glycosaminoglycan is more ingestible by a macrophage and may hence be considered to act for the promotion of conversion into foam cells.
In view of these, Lp(a) is considered to play a role in the onset and deterioration of arteriosclerosis. For ischemic heart diseases, cerebral infraction, carotid sclerosis, cerebrovascular dementia and diabetes, Lp(a) is considered to be detrimental factor.
Thus, lowering plasma levels of Lp(a) becomes a desirable therapeutic target that can reduce the risk for cardiovascular diseases in millions of people.
Despite the widely held belief that the individual plasma levels of Lp(a) are largely determined by genetic factors, there are reports showing different compounds used to affect its plasma level in humans. It has been reported that steroid hormones can lower plasma levels of Lp(a). For example, Lp(a) plasma concentrations have been shown to be influenced by the administration of anabolic steroids, progesterone and estrogen in postmenopausal women. Estrogen therapy in males with prostatic cancer reduced 50% of the plasma Lp(a). European published patent application 0 605 193 discloses anti-estrogenic and anti-androgenic agents in lowering total cholesterol and LDL levels in serum. U.S. Pat. No. 5,668,162 describes an anti-bacteria and anti-septic compound, isothiazolones, in lowering plasma Lp(a). U.S. Pat. No. 5,607,965 describes a condensed tannin existing in plants, known as proanthocyanidine, that possesses Lp(a) lowering activity. U.S. Pat. No. 5,489,611 describes organic compound, retinoids, in lowering Lp(a) levels. However, all of these compounds have significant side-effects that render their utility for long-term administration in humans questionable.
U.S. Pat. No. 5,627,172 describes creatine derivatives in lowering plasma cholesterol, lipids or lipoproteins. There is, however, no showing of this compound on plasma Lp(a). U.S. Pat. No. 5,929,091 describes a method for lowering plasma Lp(a) by inhibiting microsomal triglyceride transfer. All of the above patents are hereby incorporated in full by reference.
A safe composition therapy that can lower plasma Lp(a) is in need. We have now discovered a composition of biochemical compounds that is effective in lowering plasma Lp(a) in humans.